Mutations in the transmembrane cochlear expressed gene 1 (TMC1) underlies dominant progressive hearing loss (DFNA36) and recessive nonsyndromic sensorineural hearing loss deafness (DFNB7/B11) (Kurima et al., 2002). Similarly, semidominant and recessive alleles of Tmc1 cause hearing loss in Beethoven (Bth) and Deafness (dn) mutant mice (Vreugde et al.,2002; Kurima et al., 2002). Tmc1 is a member of the Tmc gene family that includes seven other paralogs in mammals (Keresztes et al., 2003). Tmc1 and Tmc2 are expressed in hair cells of the inner ear. We have recently demonstrated that mice that lack Tmc1 and Tmc2 are deaf and suffer profound vestibular dysfunction. Interestingly, analysis of Tmc1 and Tmc2 mRNA expression during organ of Corti development revealed a tonotopic expression pattern and a developmental switch from Tmc2 to Tmc1 (Kawashima, Gloc et al. 2011). The rise of Tmc2 mRNA expression coincided with the developmental acquisition of hair cell transduction. Analysis of transduction currents in cochlear outer hair cells of mice lacking Tmc1 or Tmc2 revealed nearly normal responses during the first postnatal week. On the other hand, hair cells from double knockout mice that lacked Tmc1 and Tmc2 did not respond to mechanical stimulation at any time point during development or in any region along the organ of Corti despite the presence of normal hair bundle morphology. Based on these observations we hypothesize that Tmc1 and Tmc2 have redundant functions and that expression of either Tmc1 or Tmc2 is required for hair cell mechanotransduction. Since Tmc2 expression is transient during the first postnatal week, the developmental switch to Tmc1 at the end of the first postnatal week could explain the deafness phenotype associated with mutations in Tmc1 in mice and humans. To explore the temporal constraints of Tmc1 and Tmc2 expression, the developmental switch in expression and their functional redundancy, we will generate several novel mouse models with conditional deletion, conditional expression and inducible expression of Tmc1 and Tmc2 and assay for changes in the properties of mechanotranduction and auditory function.